Abstract
Purpose
Analyzing the gut microbiome is essential for planning treatment strategies to manage esophageal squamous cell carcinoma. This study aimed to characterize the gut microbiome of patients with esophageal squamous cell carcinoma and to identify alterations in its composition during treatment.
Methods
We observed alterations in the gut microbiome in 21 consecutive patients with esophageal squamous cell carcinoma at five different time points, from neoadjuvant treatment to postoperative surgery. Ten healthy individuals were used as a non-cancer control group. Fecal samples were collected and analyzed using 16S ribosomal ribonucleic acid sequencing.
Results
Before treatment, participants with esophageal squamous cell carcinoma had different alpha and beta diversity in comparison to healthy controls. The number of Streptococcus, a facultative anaerobic bacterium, was significantly higher, whereas that of Faecalibacterium, an obligate anaerobic bacterium, was significantly lower. Both alpha and beta diversity remained unchanged during neoadjuvant treatment, but the alterations were pronounced after surgery. The increase in the relative abundance of Streptococcus and the decrease in that of Faecalibacterium also tended to be more pronounced after surgery.
Conclusions
The gut microbiome in patients with esophageal squamous cell carcinoma is altered with surgical intervention.
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References
Tachimori Y, Ozawa S, Numasaki H, Ishihara R, Matsubara H, Muro K, et al. Comprehensive registry of esophageal cancer in Japan, 2012. Esophagus. 2019;16:221–45.
Steevens J, Schouten LJ, Goldbohm RA, van den Brandt PA. Alcohol consumption, cigarette smoking and risk of subtypes of oesophageal and gastric cancer: a prospective cohort study. Gut. 2010;59:39–48.
Ishiguro S, Sasazuki S, Inoue M, Kurahashi N, Iwasaki M, Tsugane S, et al. Effect of alcohol consumption, cigarette smoking and flushing response on esophageal cancer risk: a population-based cohort study (JPHC study). Cancer Lett. 2009;275:240–6.
Yachida S, Mizutani S, Shiroma H, Shiba S, Nakajima T, Sakamoto T, et al. Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer. Nat Med. 2019;25:968–76.
Peters BA, Wilson M, Moran U, Pavlick A, Izsak A, Wechter T, et al. Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients. Genome Med. 2019;11:61.
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103.
Yao Q, Tang M, Zeng L, Chu Z, Sheng H, Zhang Y, et al. Potential of fecal microbiota for detection and postoperative surveillance of colorectal cancer. BMC Microbiol. 2021;21:156.
Tomita Y, Ikeda T, Sakata S, Saruwatari K, Sato R, Iyama S, et al. Association of probiotic Clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer. Cancer Immunol Res. 2020;8:1236–42.
Yamamura K, Baba Y, Nakagawa S, Mima K, Miyake K, Nakamura K, et al. Human microbiome Fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin Cancer Res. 2016;22:5574–81.
Yamamura K, Izumi D, Kandimalla R, Sonohara F, Baba Y, Yoshida N, et al. Intratumoral Fusobacterium nucleatum levels predict therapeutic response to neoadjuvant chemotherapy in esophageal squamous cell carcinoma. Clin Cancer Res. 2019;25:6170–9.
Motoori M, Yano M, Miyata H, Sugimura K, Saito T, Omori T, et al. Randomized study of the effect of synbiotics during neoadjuvant chemotherapy on adverse events in esophageal cancer patients. Clin Nutr. 2017;36:93–9.
Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Cutsem EV, Piessen G, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384:1191–203.
Deng Y, Tang D, Hou P, Shen W, Li H, Wang T, et al. Dysbiosis of gut microbiota in patients with esophageal cancer. Microb Pathog. 2021;150: 104709.
Kitagawa Y, Uno T, Oyama T, Kato K, Kato H, Kawakubo H, et al. Esophageal cancer practice guidelines 2017 edited by the Japan Esophageal Society: part 1. Esophagus. 2019;16:1–24.
Kitagawa Y, Uno T, Oyama T, Kato K, Kato H, Kawakubo H, et al. Esophageal cancer practice guidelines 2017 edited by the Japan esophageal society: part 2. Esophagus. 2019;16:25–43.
Matsuki T, Watanabe K, Fujimoto J, Takada T, Tanaka R. Use of 16S rRNA gene-targeted group-specific primers for real-time PCR analysis of predominant bacteria in human feces. Appl Environ Microbiol. 2004;70:7220–8.
Fadrosh DW, Ma B, Gajer P, Sengamalay N, Ott S, Brotman RM, et al. An improved dual-indexing approach for multiplexed 16S rRNA gene sequencing on the Illumina MiSeq platform. Microbiome. 2014;2:6.
Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods. 2010;7:335–6.
Makizaki Y, Uemoto T, Yokota H, Yamamoto M, Tanaka Y, Ohno H. Improvement of loperamide-induced slow transit constipation by Bifidobacterium bifidum G9–1 is mediated by the correction of butyrate production and neurotransmitter profile due to improvement in dysbiosis. PLoS One. 2021;16: e0248584.
Japanese Esophageal Society. Japanese classification of esophageal cancer, 11th edition: part I. Esophagus. 2017;14:1–36.
Hazra A, Gogtay N. Biostatistics series module 6: correlation and linear regression. Indian J Dermatol. 2016;61:593–601.
Takagi T, Naito Y, Inoue R, Kashiwagi S, Uchiyama K, Mizushima K, et al. The influence of long-term use of proton pump inhibitors on the gut microbiota: an age-sex-matched case-control study. J Clin Biochem Nutr. 2018;62:100–5.
Allen NE, Beral V, Casabonne D, Kan SW, Reeves GK, Brown A, et al. Moderate alcohol intake and cancer incidence in women. J Natl Cancer Inst. 2009;101:296–305.
Abranches J, Zeng L, Kajfasz JK, Palmer SR, Chakraborty B, Wen ZT, et al. Biology of oral Streptococci. Microbiol Spectr. 2018. https://doi.org/10.1128/microbiolspec.GPP3-0042-2018.
Palleja A, Kashani A, Allin KH, Nielsen T, Zhang C, Li Y, et al. Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota. Genome Med. 2016;8:67.
Ikeda T, Aida M, Yoshida Y, Matsumoto S, Tanaka M, Nakayama J, et al. Alteration in faecal bile acids, gut microbial composition and diversity after laparoscopic sleeve gastrectomy. Br J Surg. 2020;107:1673–85.
Fonseca L, Maliska CM, Cruz MG, Castro L, Gutfilen B. Esophageal reconstruction surgery in oncologic patients: determination of gastric emptying time. J Exp Clin Cancer Res. 2000;19:137–40.
Mori N, Fujita H, Sueyoshi S, Aoyama Y, Yanagawa T, Shirouzu K. Helicobacter pylori infection influences the acidity in the gastric tube as an esophageal substitute after esophagectomy. Dis Esophagus. 2007;20:333–40.
Wu J, Peters BA, Dominianni C, Zhang Y, Pei Z, Yang L, et al. Cigarette smoking and the oral microbiome in a large study of American adults. ISME J. 2016;10:2435–46.
Lopez-Siles M, Duncan SH, Garcia-Gil LJ, Martinez-Medina M. Faecalibacterium prausnitzii: from microbiology to diagnostics and prognostics. ISME J. 2017;11:841–52.
Bjørkhaug ST, Aanes H, Neupane SP, Bramness JG, Malvik S, Henriksen C, et al. Characterization of gut microbiota composition and functions in patients with chronic alcohol overconsumption. Gut Microbes. 2019;10:663–75.
Chaput N, Lepage P, Coutzac C, Soularue E, Roux KL, Monot C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28:1368–79.
Hibberd AA, Lyra A, Ouwehand AC, Rolny P, Lindegren H, Cedgård L, et al. Intestinal microbiota is altered in patients with colon cancer and modified by probiotic intervention. BMJ Open Gastroenterol. 2017;4: e000145.
Martini G, Ciardiello D, Dallio M, Famiglietti V, Esposito L, Corte CMD, et al. Gut microbiota correlates with antitumor activity in patients with mCRC and NSCLC treated with cetuximab plus avelumab. Int J Cancer. 2022;151(3):473–80.
Nishijima S, Suda W, Oshima K, Kim SW, Hirose Y, Morita H, et al. The gut microbiome of healthy Japanese and its microbial and functional uniqueness. DNA Res. 2016;23(2):125–33.
García-Solache M, Rice LB. The Enterococcus: a model of adaptability to its environment. Clin Microbiol Rev. 2019. https://doi.org/10.1128/CMR.00058-18.
Shi W, Shen L, Zou W, Wang J, Yang J, Wang Y, et al. The gut microbiome is associated with therapeutic responses and toxicities of neoadjuvant chemoradiotherapy in rectal cancer patients-a pilot study. Front Cell Infect Microbiol. 2020;10: 562463.
Acknowledgements
We would like to thank all of the participants. We would also like to thank Editage (www.editage.com) for editing the English language of this manuscript. This work was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI [Grant Number JP20K09035].
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All authors contributed to the study’s conception and design. HH: collected data and samples and wrote the first draft of the manuscript; YM, HY, YT, and HO: analyzed the gut microbiome data; MS: contributed intellectual inputs, mainly for statistics; HM: collected data and samples; YK: contributed intellectual inputs, mainly for treatment; TI, EO, and TY: supervised the entire study. All authors participated in writing the manuscript and/or critically revising the content. All authors approved the final manuscript.
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Hasuda, H., Ikeda, T., Makizaki, Y. et al. Alterations in the gut microbiome in patients with esophageal carcinoma in response to esophagectomy and neoadjuvant treatment. Surg Today 53, 663–674 (2023). https://doi.org/10.1007/s00595-022-02607-3
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DOI: https://doi.org/10.1007/s00595-022-02607-3